Project Summary/Abstract Our overarching goal is to define the molecular mechanisms underpinning the actions of VA compounds. Our overall objective in the studies proposed here, which represent the next step in pursuing this goal, is to define the impact and mechanisms of volatile anesthetics on tissue-specific and circulating metabolism in conditions where volatile anesthetics carry known risks of morbidity and in states of metabolic ketosis. Volatile anesthetics are invaluable tools in modern medicine. Despite their prevalent use, the precise molecular mechanisms of volatile anesthetic (VA) activity remain largely unclear. Where data are available, a complex picture emerges. Experimental evidence has revealed multiple direct targets mediating both the anesthetic/sedative and non-anesthesia related effects of these agents, including neuro-receptors, ion channels, and mitochondrial electron transport chain complex I (ETC CI). Among known molecular targets of VA?s, the relative contributions of each to the functional effects of VAs is poorly understood. VAs are generally regarded as devoid of long term sequelae, but specific populations of patients are at risk for intrinsic detrimental effects of VAs. For example, both extremes of age are sensitive to CNS damage following anesthetic exposure. Additionally, patients with primary mitochondrial disorders are hypersensitive to VAs; the literature harbors multiple reports of children with mitochondrial disease who have died after a routine anesthetic. Unexplained extreme responses to VAs are rare, but also remain a source of concern in clinical practice. Understanding the mechanisms underlying negative responses to anesthesia may lead to improved patient screening, monitoring, and care. At-risk populations may benefit most from this knowledge, but, given that all VAs have off target effects that may impact patient outcomes, understanding their mechanisms may lead to safer practices throughout the field. The goal of this proposal is to define impact and mechanisms of volatile anesthetics on tissue-specific and circulating metabolism in conditions where volatile anesthetics carry known risks of morbidity, and the potential therapeutic benefit of intervening in altered metabolism. We hypothesize that altered metabolism mediates multiple sequelae of VA exposure in sensitive populations, including both toxicity and neurocognitive deficits in sensitive settings. Defining the role of VA exposure on metabolism will provide new insights into these complex drugs.